1. Itch and Inflammation.
The phenomenon of itching is a widespread source of discomfort and annoyance, and the search for relief has created a significant market for products intended to alleviate the problem. To address this need, a tremendous number of topical products have been released onto the market over the years. These formulations generally contain, in addition to their inert bases, one or more of three classes of active ingredients: anti-histamines, steroids, and anesthetics. There is also available a class of “natural” lotions which utilize components derived from natural sources such as oatmeal and aloe vera; extracts and oils such as menthol, tea oil, and coriander oil; and herbal extracts such as arnica, willow bark, witch hazel and others.
A common home remedy for itch, irritation, and dermal pain is an aqueous paste of meat tenderizer, which is typically applied to insect bites and jellyfish stings to relieve the pain and itch associated with these injuries. The principal ingredient in these products is an enzyme-containing extract from either papaya or pineapple.
The majority of commercially available anti-histamines, steroids, and topical anesthetics are synthetic compounds, which many consumers prefer to avoid if possible. Accordingly, there remains a need for naturally-derived, topical agents capable of safely relieving itch and irritation.
2. Erythema and Inflammation in Allergic and Atopic Dermatitis, Rosacea and Psoriasis.
Rosacea is a chronic condition which is characterized by facial erythema and occasionally red domed papules and pustules. Four subtypes (Phymatous, Erythematotelangiectatic, Papulopustular, and Ocular) and three variants (conglobate, fulminans, and phymatous) of rosacea have been identified. Since there is no specific test for rosacea, it is generally diagnosed by visual inspection and it is currently treated with oral and topical antibiotics, alpha-hydroxy acid peels and dermatological laser treatment (N. Scheinfeld, T. Berk, “A Review of the Diagnosis and Treatment of Rosacea” Postgraduate Medicine 2010, 122(1): 139-143; E. J. van Zuuren et al., “Interventions for rosacea” Cochrane Database of Systematic Reviews 2015, Issue 4, Art. No. CD003262.) Rosacea has no cure, and lifelong treatment for relief of symptoms is often necessary (B. Culp, N. Scheinfeld, “Rosacea: A Review” Pharmacy & Therapeutics 2009, 34(1): 38-45.)
The term “eczema” refers to a set of clinical observations; it is commonly used as a generic term for various forms of dermatitis, including atopic and contact dermatitis. Recent studies have shown that a member of the cathelicidin family of host defense peptides, LL-37, is expressed in small amounts in humans but accumulates in skin affected by diseases such as atopic dermatitis (P. Y. Ong et al., “Endogenous Antimicrobial Peptides and Skin Infections in Atopic Dermatitis” N Engl. J. Med. 2002, 347(15): 1151-1160) rosacea (K. Yamasaki et al., “Increased serine protease activity and cathelicidin promotes skin inflammation in rosacea” Nature Med. 2007, 13:975-980) and psoriasis. In addition, the IL-19 cytokine is reportedly over-produced in psoriasis patients (E. Witte et al., “IL-19 Is a Component of the Pathogenetic IL-23/IL-17 Cascade in Psoriasis” J. Invest. Dermatol. 2014, 134:2757-2767.) Evidence is also mounting for the involvement of mast cells in rosacea (Y. Muto et al., “Mast Cells Are Key Mediators of Cathelicidin-Initiated Skin Inflammation in Rosacea” J. Invest. Dermatol. 2014, 134:2728-2736.)
The above-cited studies, and numerous others, have established a connection between dermatological diseases and the over-expression of endogenous peptides. Topical compositions which reduce the amounts of these peptides may therefore provide relief from the symptoms of rosacea, psoriasis, eczema, and related dermatological conditions.
3. Papain and Bromelain.
Papain is a cysteine protease (papaya proteinase I, EC 3.4.22.2) extracted from the unripe fruit of the papaya plant (Carica papaya). Bromelain may be either of two broadly-defined cysteine proteases (stem bromelain, EC 3.4.22.32, and fruit bromelain, EC 3.4.22.33) extracted from the plants of the family Bromeliaceae (pineapple.) In commerce, the term may refer to a crude plant extract (a lyophilized, filtered plant juice, acetone powder, or the like) containing both enzymes, although, with most of the fruit being harvested for market, the stem enzyme is most prevalent. Both enzymes are well-known as components of enzymatic compositions for dermal debridement and exfoliation. Their use as oral anti-inflammatory agents has been sporadically described in the literature.
U.S. Pat. No. 3,860,702 discloses a suspension of papain in partially hydrolyzed cocoa butter, useful as a topical anti-inflammatory. Recently, Valeant Pharmaceuticals Australia introduced Stop Itch Plus™, a first aid cream formulated with papain. The product is claimed to relieve itching caused by insect bites, minor burns, cuts, scratches, sunburn and windburn.
U.S. Pat. No. 5,441,740 describes cosmetic compositions containing alpha-hydroxy acids, salicylic acid and mixtures of bromelain and papain for use as dermal exfoliating agents. The compositions are said to be useful for the treatment of skin conditions such as lack of adequate skin firmness, wrinkles, and dry skin. The utility of bromelain for relief from itch and other irritation is not disclosed.
U.S. Patent Application Publication No. 2005/0249720 describes cosmetic formulations of honey and a blend of natural fruits including pineapple, mango, and papaya as active dermal exfoliating agents.
U.S. Pat. Nos. 4,197,291, 4,329,430, 5,387,517, 5,830,739 and 8,119,124 and U.S. Patent Application Publication No. 2013/0156745 also describe bromelain-derived compositions for the enzymatic debridement of burns and wounds.
U.S. Pat. No. 6,579,543 describes topical compositions comprising, among a wide variety of ingredients, at least one compound “having anti-inflammatory activity,” and among the many named anti-inflammatory agents is bromelain. The compositions are said to have “analgesic, anti-inflammatory, antioxidant, anti-neuralgic, blood circulation promotion and antidepressant activities,” and are allegedly useful for relief from a wide array of “conditions or injuries that cause a subject discomfort,” including poison ivy and insect stings and bites.
The U.S. Food and Drug Administration (FDA) in 2008 ordered a halt to the marketing of unapproved drug products that contain papain in a topical dosage form (including Stop Itch Plus™), because the drugs can produce harmful or near-fatal effects, hypersensitivity resulting in anaphylactic reactions being the primary concern. The agency cited cases resulting in cardiovascular symptoms such as hypotension and tachycardia, some requiring emergency rooms visits and treatment with epinephrine. The FDA also asserted that the effectiveness of the products was not supported by scientifically sound studies in the medical literature.
Extracts of Ananas comosus (pineapple) stem contain at least eight different proteolytic enzymes (T. Harrach et al., “Isolation and partial characterization of basic proteinases from stem bromelain,” 1995, J. Protein Chem. 14:41-52.) The crude, unseparated enzyme mixture is commonly referred to as “bromelain”. Bromelain has a proteolytic profile that is distinct from that of papain (A. Ritonja et al., “Stem bromelain: amino acid sequence and implications for weak binding of cystatin” 1989, FEBS Letters 247:419-424.) Bromelain has long had a variety of reputed uses in folk medicine, and it remains a subject of continual investigation by the alternative medicine community. Numerous bromelain-based “dietary supplements” are marketed for oral consumption, and low levels of bromelain have been incorporated into “natural” cosmetic and analgesic creams and lotions. Non-clinical studies have suggested that bromelain may block proinflammatory metabolites, and that it may affect migration of neutrophils by stripping away cell-surface receptors and ligands. No such effects have ever been confirmed in human studies, however, and with the exception of a burn debridement product (NexoBrid™), bromelain is not approved with a health claim for any disorder by the FDA or by the European Medicines Agency. The U.S. National Institutes of Health rates bromelain as “possibly effective” against osteoarthritis when taken orally, in combination with trypsin and rutin, but no evidence indicates utility or efficacy of bromelain for any other disorder.